New publication from the lab: Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26
The TRIM-NHL protein Meiotic-P26 acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes and spermatogenesis. Together with our collaborators from the Glatt lab (Max Planck Research Group at the Malopolska Centre of Biotechnology, Jagiellonian University Krakow, Poland) and the Bujnicki lab (Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Poland), we could solve the first high resolution structure of the Mei-P26 NHL domain and define a consensus RNA motif that it recognizes. Molecular dynamics simulations allowed us to predict and subsequently experimentally validate key amino acid residues involved specific RNA recognition, highlighting differences to other NHL domains. Using individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP), we could identify RNA targets of Mei-P26 in cultured Drosophila cells and demonstrate the protein can either repress or activate its genuine mRNA targets. Regulation requires the NHL domain of the protein but is independent of its function as a ubiquitin ligase.
In particular, the last finding significantly expands our understanding of TRIM-NHL protein-mediated gene regulation. These proteins were previously considered to exclusively act as repressors of gene expression. Strikingly, Mei-P26 itself appears to lack any regulatory activity suggesting that the regulatory outcome is determined by the recruitment of different co-factors, some of which have previously been identified by genetic means.
A preprint of the manuscript is available at bioRxiv (doi.org/10.1101/2021.09.20.461029)